The direct non-endocytotic uptake of cholesteryl esters (CE) from high density lipoprotein (HDL) plays a major role in HDL CE metabolism in rats and rabbits. In vitro evidence indicates it may also play such a role in humans. However, a study in mice (tracing the CE and apoA-I moieties of HDL) concluded that, while selective uptake played a role in normal animals, it did not in transgenic mice which express predominantly human apoA-I (Chajek-Shaul et al., 1991. Proc. Natl. Acad. Sci. USA. 88: 6731-6735);thus human apoA-I was apparently unable to support selective uptake. These conclusions rested on plasma decay data that represent a composite of all tissue and which may obscure tissue-specific factors. Thus we reexamined the matter by measuring the rates of uptake of HDL components by individual tissues using intracellularly trapped tracers. Plasma decay data were much as reported in the referenced study. Nonetheless the fractional rate of uptake of HDL CE was greater than that of apoA-I in adrenal gland and liver, indicating selective uptake. Kidney took up apoA-I tracer at a greater fractional rate than CE tracer, apparently by filtration and reabsorption of free apoA-I, and this uptake was at a greater fractional rate in the transgenic mice than in normal mice. Thus, the lack of evidence for selective uptake in the plasma decay data of the transgenic mice was explained by a higher rate of renal uptake of apoA-I and not by a diminished rate of selective uptake in other tissues.(ABSTRACT TRUNCATED AT 250 WORDS)